selumetinib

Absorption: 62% absorbed following oral administration.

Distribution: Extensively distributed to tissues.

Protein Binding: 96%.

Metabolism/Excretion: Primarily metabolized by CYP3A4 isoenzyme and to a lesser extent by CYP2C19, CYP1A2, CYP2C9, CYP2E1, and CYP3A5 (converted to active metabolite via CYP2C19 and CYP1A2); also undergoes glucuronidation by UGT1A1 and UGT1A3. Primarily excreted in feces (59%; 19% as unchanged drug), with 33% being excreted in urine (<1% as unchanged drugs).

Half-Life: 6.2 hr.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	1–1.5 hr	12 hr

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Severe hepatic impairment;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

HF;
Moderate hepatic impairment (↓ dose);
Rep: Women of reproductive potential and men with female partners of reproductive potential;
Pedi: Children <2 yr (safety and effectiveness not established).

Adv. Reactions/Side Effects ⬆ ⬇

CNS: headache

CV: edema, tachycardia, cardiomyopathy, hypertension

Derm: alopecia, dry skin, hair color changes, paronychia, pruritus, rash, skin infection, palmar-plantar erythrodysesthesia syndrome

EENT: epistaxis, blurred vision, cataracts, ocular hypertension, photophobia, retinal pigment epithelial detachment (RPED), retinal vein occlusion, visual impairment

F and E: hyperkalemia, hypernatremia, hypokalemia, hyponatremia

GI: ↑amylase, ↑lipase, ↑liver enzymes, abdominal pain, constipation, diarrhea, hypoalbuminemia, nausea, stomatitis, vomiting, colitis, dry mouth, GI OBSTRUCTION, GI PERFORATION, ILEUS

GU: hematuria, proteinuria, acute kidney injury

Hemat: anemia, lymphocytopenia, NEUTROPENIA

Metab: ↓appetite, weight gain

MS: ↑CK, myalgia, RHABDOMYOLYSIS

Resp: dyspnea

Misc: fatigue, fever

Interactions ⬆ ⬇

Drug-drug:

Strong CYP3A4 inhibitors, including itraconazole and moderate CYP3A4 inhibitors, including erythromycin and fluconazole, may ↑ levels and risk of toxicity; avoid concurrent use; if concurrent use cannot be avoided, ↓ selumetinib dose.
Strong CYP3A4 inducers, including rifampin, and moderate CYP3A4 inducers, including efavirenz, may ↓ levels and effectiveness; avoid concurrent use.
May ↑ the risk of bleeding with warfarin, aspirin, clopidogrel, prasugrel, or ticagrelor.

Route/Dosage ⬆ ⬇

PO (Children ≥2 yr and body surface area [BSA] ≥1.90 m²): 25 mg/m²(50 mg) twice daily. Concurrent use of strong CYP3A4 inhibitor, moderate CYP3A4 inhibitor, or fluconazole: If current dose 25 mg/m² twice daily, ↓ to 20 mg/m² (40 mg) twice daily; if current dose 20 mg/m² twice daily, ↓ to 15 mg/m² (30 mg) twice daily.
PO (Children ≥2 yr and BSA = 1.70–1.89 m²): 25 mg/m²(45 mg) twice daily. Concurrent use of strong CYP3A4 inhibitor, moderate CYP3A4 inhibitor, or fluconazole: If current dose 25 mg/m² twice daily, ↓ to 20 mg/m² (35 mg) twice daily; if current dose 20 mg/m² twice daily, ↓ to 15 mg/m² twice daily (30 mg in AM and 25 mg in PM).
PO (Children ≥2 yr and BSA = 1.50–1.69 m²): 25 mg/m² (40 mg) twice daily. Concurrent use of strong CYP3A4 inhibitor, moderate CYP3A4 inhibitor, or fluconazole: If current dose 25 mg/m² twice daily, ↓ to 20 mg/m² twice daily (35 mg in AM and 30 mg in PM); if current dose 20 mg/m² twice daily, ↓ to 15 mg/m² (25 mg) twice daily.
PO (Children ≥2 yr and BSA = 1.30–1.49 m²): 25 mg/m² (35 mg) twice daily. Concurrent use of strong CYP3A4 inhibitor, moderate CYP3A4 inhibitor, or fluconazole: If current dose 25 mg/m² twice daily, ↓ to 20 mg/m² twice daily (30 mg in AM and 25 mg in PM); if current dose 20 mg/m² twice daily, ↓ to 15 mg/m² twice daily (25 mg in AM and 20 mg in PM).
PO (Children ≥2 yr and BSA = 1.10–1.29 m²): 25 mg/m² (30 mg) twice daily. Concurrent use of strong CYP3A4 inhibitor, moderate CYP3A4 inhibitor, or fluconazole: If current dose 25 mg/m² twice daily, ↓ to 20 mg/m² (25 mg) twice daily; if current dose 20 mg/m² twice daily, ↓ to 15 mg/m² twice daily (25 mg in AM and 10 mg in PM).
PO (Children ≥2 yr and BSA = 0.90–1.09 m²): 25 mg/m² (25 mg) twice daily. Concurrent use of strong CYP3A4 inhibitor, moderate CYP3A4 inhibitor, or fluconazole: If current dose 25 mg/m² twice daily, ↓ to 20 mg/m² (20 mg) twice daily; if current dose 20 mg/m² twice daily, ↓ to 15 mg/m² twice daily (20 mg in AM and 10 mg in PM).
PO (Children ≥2 yr and BSA = 0.70–0.89 m²): 25 mg/m² (20 mg) twice daily. Concurrent use of strong CYP3A4 inhibitor, moderate CYP3A4 inhibitor, or fluconazole: If current dose 25 mg/m² twice daily, ↓ to 20 mg/m² twice daily (20 mg in AM and 10 mg in PM); if current dose 20 mg/m² twice daily, ↓ to 15 mg/m² (10 mg) twice daily.
PO (Children ≥2 yr and BSA = 0.55–0.69 m²): 20 mg in AM and 10 mg in PM. Concurrent use of strong CYP3A4 inhibitor, moderate CYP3A4 inhibitor, or fluconazole: If current dose 25 mg/m² twice daily, ↓ to 20 mg/m² (10 mg) twice daily; if current dose 20 mg/m² twice daily, ↓ to 15 mg/m² (10 mg) once daily.

Hepatic Impairment

PO (Children ≥2 yr): Moderate hepatic impairment: BSA ≥1.90 m²: 40 mg twice daily; BSA = 1.70–1.89 m²: 35 mg twice daily; BSA = 1.50–1.69 m²: 35 mg in AM and 30 mg in PM; BSA = 1.30–1.49 m²: 30 mg in AM and 25 mg in PM; BSA = 1.10–1.29 m²: 25 mg twice daily; BSA = 0.90–1.09 m²: 20 mg twice daily; BSA = 0.70–0.89 m²: 20 mg in AM and 10 mg in PM; BSA = 0.55–0.69 m²: 10 mg twice daily.

Availability ⬆ ⬇

Capsules: 10 mg (contains 32 mg vitamin E); 25 mg (contains 36 mg vitamin E)

Assessment ⬆ ⬇

Monitor BP at baseline and periodically; may ↑ BP.
Monitor for signs and symptoms of bleeding (fatigue, pallor of skin or conjunctiva, dyspnea, tachycardia, anemia). Treat as clinically indicated.
Monitor for signs and symptoms of ileus (abdominal distention, constipation) or GI perforation (nausea, abdominal pain, tarry stools, coffee ground emesis, pallor, anemia). Treat as clinically indicated.
Monitor for diarrhea; therapy interruption, dosage adjustment, or permanent discontinuation may be recommended.
Assess left ventricular ejection fraction (LVEF) by echocardiogram prior to initiating treatment, every 3 mo during the first yr of treatment, every 6 mo thereafter, and as clinically indicated. If asymptomatic ↓ in LVEF of ≥10% from baseline and <lower level of normal, hold selumetinib until resolution; then resume at ↓ dose. Permanently discontinue selumetinib in patients unable to tolerate after two dose ↓.
Monitor for signs and symptoms of rhabdomyolysis (malaise, myalgia, muscle cramps or weakness, dark or tea-colored urine). If any ↑ CK plus myalgia or Grade 4 ↑ CK occurs, hold selumetinib until ≤Grade 1; then resume at ↓ dose. Permanently discontinue selumetinib if no improvement within 3 wk or if unable to tolerate after two dose ↓.
Conduct comprehensive ophthalmic assessments prior to initiating therapy, at regular intervals during treatment, and for new or worsening visual changes. Monitor for signs and symptoms of ocular toxicities such as cataracts, retinal vein occlusion, or RPED (blurred vision, photophobia, ocular hypertension). If RPED occurs, withhold selumetinib until resolution; then resume at ↓ dose. Permanently discontinue selumetinib in patients unable to tolerate after two dose ↓. If retinal vein occlusion occurs, permanently discontinue selumetinib.
Monitor for signs and symptoms of severe skin rash, including palmar-plantar erythrodysesthesia syndrome (itching, burning, numbness, tingling, thick calluses or blisters on the palms of the hands or soles of the feet), which can occur within 2–3 mo of taking the medication; dosage adjustment or permanent discontinuation may be necessary. If Grade 3 or 4 skin toxicity occurs, hold selumetinib until improvement; then resume at ↓ dose. Permanently discontinue selumetinib in patients unable to tolerate after two dose ↓.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.
Monitor serum CK prior to initiating treatment, periodically during therapy, and as clinically indicated.

Implementation ⬆ ⬇

PO: Administer twice daily on an empty stomach. Food should not be consumed 2 hr before each dose or 1 hr after each dose. DNC: Swallow capsules whole with water; do not chew, dissolve, or open capsule. If dose vomited, hold and continue with the next scheduled dose. Do not administer a missed dose unless it is >6 hr until the next scheduled dose.
Dose Reduction Schedule: BSA 0.55–0.69 m²: 1st reduction: 10 mg twice daily; 2nd reduction: 10 mg daily; BSA 0.7–0.89 m ²: 1st reduction: 20 mg AM and 10 mg PM; 2nd reduction: 10 mg twice daily; BSA 0.9–1.09 m²: 1st reduction: 25 mg AM and 10 mg PM; 2nd reduction: 10 mg twice daily; BSA 1.1–1.29 m ²: 1st reduction: 25 mg AM and 20 mg PM; 2nd reduction: 20 mg AM and 10 mg PM; BSA 1.3–1.49 m ²: 1st reduction: 25 mg twice daily; 2nd reduction: 25 mg AM and 10 mg PM; BSA 1.5–1.69 m ²: 1st reduction: 30 mg twice daily; 2nd reduction: 25 mg AM and 20 mg PM; BSA 1.7–1.89 m ²: 1st reduction: 35 mg AM and 30 mg PM; 2nd reduction: 25 mg AM and 20 mg PM; BSA ≥1.9 m ²: 1st reduction: 35 mg twice daily; 2nd reduction: 25 mg twice daily. Permanently discontinue selumetinib in patients unable to tolerate after two dose ↓.

Patient/Family Teaching ⬆ ⬇

Explain purpose and side effects of selumetinib. Instruct patient to take drug on an empty stomach ≥2 hr before or 1 hr after a meal and to refrain from taking a missed dose unless it is >6 hr until the next scheduled dose. If dose is vomited, an additional dose should not be taken and patient should continue with next scheduled dose. Advise patient to read Patient Information before starting therapy.
Explain need for continued medical follow-up to assess effectiveness and possible side effects of medication. Periodic lab tests, echocardiogram, and eye exams may be needed.
Advise patient to immediately report symptoms of cardiomyopathy (fatigue, swelling of abdomen or legs, trouble breathing, chest pain).
Advise patient to immediately report symptoms of rhabdomyolysis (feeling tired or ill, muscle aches, muscle cramps or weakness, dark or tea-colored urine).
Instruct patient to report any eye symptoms or vision changes, GI symptoms (nausea, vomiting, bloating, constipation, abdominal pain or distention), or skin rash.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking other medications; avoid grapefruit products, St. John's wort, and vitamin E.
Rep: May cause fetal harm; patients and partners of reproductive potential should use effective contraception during treatment and for 1 wk after the last dose. Advise women not to breastfeed during treatment with selumetinib and for 1 wk after the last dose.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇